Celiac disease (CD) is an autoimmune disorder that results from an inflammatory reaction to gluten in the diet (found in wheat, barley and rye) that often causes damage to the small intestine but can affect other organs as well. CD can arise at any age and typically presents with a broad spectrum of symptoms. CD is the only autoimmune disease with a known etiology which is related to a permanent intolerance to gluten. It occurs in those with a genetic predisposition and resolves with exclusion of gluten from the diet. It often, but not always, leads to autoimmunity against the small intestine, resulting in chronic intestinal inflammation and destruction of intestinal tissue. However, it can affect other organs as well, such as the brain, bone and skin, thus making it a systemic disease rather than a disease limited to the gastrointestinal tract.
There has been a substantial increase in the prevalence of CD over the last 50 years and an increase in the rate of diagnosis in the last 10 years. The prevalence of CD is still only about 1% in the general population. However, CD is thought to be largely underdiagnosed, in part owing to the fact that celiac disease is often characterized by associated conditions and extraintestinal manifestations that can misdirect and impede diagnosis.
Signs and Symptoms
“Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g. diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) but also non-gastrointestinal abnormalities (e.g. abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, neurological abnormalities, and many other…manifestations).”
“…for every symptomatic patient with CD there are eight patients with CD and no gastrointestinal symptoms.”
Symptoms of CD vary widely and often do not involve the GI tract. Common abdominal symptoms include gas, bloating, diarrhea and abdominal pain. Weight loss and malabsorption syndrome are common manifestations due to damage to the intestinal lining where nutrients are absorbed. It may also manifest as nutritional deficiencies leading to osteoporosis, iron-deficient anemia or vitamin B12 deficiency. CD can also manifest as skin lesions, or neurological symptoms such as numbness and tingling, balance and coordination problems, brain fog or depression. Often the symptoms are mild or dismissed as unimportant. A significant proportion (40% to 60%) of individuals with celiac disease may have mild or absent symptoms. In addition to autoimmunity against the gastrointestinal tract, celiac disease (CD) can manifest as autoimmunity against the brain (cerebellar ataxia) and skin (dermatitis herpetiformis), thus making it a systemic autoimmune disease (AD) rather than an autoimmune disease limited to the GI tract.
“Celiac disease is one of the most common causes of chronic malabsorption. This results from injury to the small intestine with loss of absorptive surface area, reduction of digestive enzymes, and consequential impaired absorption of micronutrients such as fat-soluble vitamins, iron and potentially B12 and folic acid. In addition, the inflammation exacerbates symptoms of malabsorption by causing net secretion of fluid that can result in diarrhea. The failure of absorption of adequate calories leads to weight loss, and the malabsorption results in abdominal pain and bloating.”
In addition to symptoms involving the intestinal tract, celiac disease can lead to extraintestinal manifestations that can affect multiple organ systems. Some of these manifestations are direct consequences of autoimmunity against other tissues of the body such as the cerebellum of the brain or the skin. Other manifestations are indirectly related to inflammation and/or malabsorption including anemia, osteoporosis, short stature and delayed puberty. Any organ from the central nervous system to joints, liver or teeth can be affected. In some cases, extraintestinal symptoms are the only clinical manifestations of celiac disease or occur in conjunction with diarrhea and malabsorptive symptoms.
“An increased awareness among medical practitioners of the variety of extraintestinal manifestations of celiac disease is essential to improve diagnosis and treatment.”
“Celiac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of celiac disease and autoimmunity have been gained.”
“The comorbidity between celiac disease and other autoimmune disorders has been clearly established.”
“The strongest associations between CD and systemic autoimmune diseases include Addison’s disease, autoimmune thyroid disease, autoimmune insulin-dependent diabetes mellitus, Sjogren’s syndrome, primary biliary cirrhosis and autoimmune hepatitis.”
CD is associated with a number of autoimmune conditions, such as autoimmune liver disease, autoimmune thyroiditis, Sjogren’s syndrome, systemic lupus erythematosus (SLE), Addison’s disease, rheumatoid arthritis (RA), psoriasis and type 1 diabetes. A significantly increased prevalence of these autoimmune diseases (AD) have been reported in individuals with CD and their first-degree relatives as compared to controls, with an estimated increase of incidence of AD affecting up to 15% of CD cases. The causes for the onset and manifestation of associated diseases are diverse. Some conditions share a similar genetic base, like type 1 diabetes (T1D); others share pathogenic mechanisms, and yet, others are of unknown nature. It has been suggested that these associations among CD and other AD may be explained by the sharing of a common pathogenic basis involving genetic susceptibility, environmental triggers (ie: gluten), and the loss of intestinal barrier function secondary to dysfunction of intestinal tight junctions leading to increased intestinal permeability..
“General practitioners and other specialists must remember that CD may manifest with extraintestinal manifestations, and associated illnesses may appear both at the time of diagnosis and throughout the evolution of the disease.”
“…while disease pathogenesis and pathophysiology remain incompletely understood, the disease is thought to arise from the interplay of genetic, environmental (ie: ingestion of gluten) and immunological factors.”
Celiac disease has a strong hereditary component. Epidemiological studies show that up to 20% of first-degree relatives are affected by the disease with incidence of CD of 75–80% in monozygotic twins. The strongest and best-characterized genes in celiac disease are human leukocyte antigen (HLA) class II genes known as HLA-DQ2 and HLA-DQ8, molecules responsible for presentation of antigens to immune cells. However, while HLA-DQ2 or DQ8 are necessary for disease to develop, they are not sufficient, implicating other genetic or environmental factors in disease development. Approximately, 25–30% of individuals of European descent carry HLA-DQ2 susceptibility, but only about 4% of these individuals will develop CD in their lifetime highlighting the important role of non-genetic factors.
Environmental factors clearly play an important role in the pathogenesis of CD. The primary trigger in CD is gluten, and, over the past decade, many studies have contributed to our understanding of gluten biochemistry and antigens, transport of these antigens through the small intestinal epithelium, modification by enzymes in the gut, including tissue transglutaminase (tTG), and binding to antigen presenting cells in the basement membrane with subsequent activation of adaptive immunity. It has become clear that gluten is associated with innate immune responses in the gut and that cytotoxic lymphocytes in the gut epithelium appear to play a central role.
“…epidemiological studies have suggested that early gluten introduction to children, ceasarean section delivery as well as lack of breast-feeding are important risk factors for development of celiac disease.”
In addition, emerging data implicates microbiota (both commensal and pathogenic bacteria) in disease pathogenesis, while epidemiological studies have suggested that early gluten introduction to children, ceasarean section delivery as well as lack of breast-feeding are important risk factors for development of celiac disease. Let’s take a brief look at what gluten actually is and where it comes from.
“Wheat, barley and rye belong to the same tribe of plants called triticeae that diverged from oats belonging to the aveneae tribe. While “gluten” is used as the general term to describe the trigger of celiac disease, gluten technically refers to the disease-activating peptides found only in wheat.”
Gluten is comprised of two different protein types, gliadins and glutenins, capable of triggering disease. The peptides in barely and rye are called hordeins and secalins respectively, and are also capable of activating disease. In contrast, oats, comprised of more distantly related peptides called avenins, rarely trigger CD. These compounds from wheat, barley and rye contain high contents of prolines and glutamines which make them resistant to digestion by gastric acid and intestinal enzymes in the human digestive tract. This means that these proteins cannot be completely digested by humans because we lack the enzymes required in order to break these proteins down completely.[687,688]
“Gliadins, glutenins, hordein and secalins contain high contents of prolines and glutamines which makes them resistant to degradation by gastric acid, pancreatic and brush border enzymes because these are lacking in prolyl endopeptidase activity.”
Normally, protein fragments that have not been completely digested (broken down) do not cross the epithelial lining of the intestinal tract. They pass on through the GI tract and are eliminated from the body since the epithelial lining serves as a barrier and prevents the absorption of undigested proteins. However, in CD, undigested protein fragments can be transported across the epithelial lining of the intestines. The tight junctions (TJs) of the epithelial lining play a role in peptide transport and genome-wide association studies in celiac disease have found certain genetic defects (SNPs) in tight junction-associated genes.[689,690] Transport of peptide fragments across the small intestinal epithelium and intestinal permeability have been areas of intense research in CD, though their primary role in disease pathogenesis remains incompletely understood.
It is unclear whether altered intestinal permeability is a primary cause or a consequence of intestinal inflammation seen in CD. The role of tight junction blockade as a therapeutic strategy for CD is currently being studied by researchers.[691-693] Further study is required to determine the role of peptide fragment transport and intestinal permeability in pathogenesis of CD. Understanding of CD pathophysiology, in which the trigger (wheat, rye and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (e.g., type I diabetes) that share many common pathophysiologic imbalances.
“These figures suggest that the current ratio (prevalence based) of clinically diagnosed to undetected cases—that is, “the size of the iceberg”—in the UK is approximately 1 in 8.” 
The vast majority of patients with CD remain undiagnosed. It is estimated that only 1 in 8 patients have clinically diagnosed celiac disease (12.5%) which has been referred to in the literature as the ‘tip of the iceberg’. The majority of CD patients (87.5%) have undiagnosed silent celiac disease and patients are asymptomatic. Let’s look at the specific serologic tests doctors use to screen for CD.
CD is usually detected by serologic testing of celiac-specific antibodies. IgA anti-tissue transglutaminase antibody (tTG-IgA) is the preferred single test for detection of CD in individuals over the age of 2 years. The sensitivity of the tTG-IgA for untreated CD is about 95% and the specificity is also 95% or greater. When there exists a high probability of CD in a negative tTG-IgA test, the possibility of IgA deficiency is considered and total IgA should be measured. An alternative approach is to include both IgA and IgG based testing, such as IgG deamidated gliadin peptides [DGP], in these high probability patients. In patients in whom low IgA or selective IgA deficiency is identified, IgG-based testing (IgG deamidated gliadin peptides [DGP] and IgG tissue transglutaminase [TTG]) should be performed. The diagnosis is confirmed by duodenal mucosal biopsies. If the suspicion of CD is high, intestinal biopsy should be pursued even if serologies are negative. Both serology and biopsy should be performed on a gluten-containing diet.
The treatment for celiac disease in conventional medicine is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood.
“The implementation of GFD improves the overall clinical course and influences the evolution of the associated diseases. In some cases, such as iron deficiency anemia, the GFD contributes to its disappearance. In other disorders, like type 1 diabetes, this allows a better control of the disease. In several other complications and/or associated diseases, an adequate adherence to a GFD may slow down their evolution, especially if implemented during an early stage.”
In addition to ensuring the patient is on a gluten-free diet (GFD), the FM practitioner will consider the assessment of associated conditions such as intestinal permeability and a comprehensive stool analysis to rule out other coexisting GI conditions such as dysbiosis, pathogenic infection and inflammatory bowel disease (IBD). In addition to CD, these conditions should be assessed and addressed when any abnormalities are found. The practitioner should also look for signs and symptoms of other autoimmune conditions commonly seen in CD, such as autoimmune thyroiditis (Hashimoto’s and Grave’s disease), pernicious anemia, RA, SLE and type 1 diabetes. Testing for gluten-associated cross-reactivity from other foods should also be considered. Cyrex Labs offers an excellent test for this purpose.
In addition to minimizing intake of gluten and gluten-associated cross-reactive foods, management should include immunomodulatory supplement support for normal immune responses, as in inflammatory bowel disease (IBD). These include compounds such as vitamin D, glutathione, turmeric, resveratrol and omega-3 essential fatty acids (see FM Management of IBD section above). Gluten-digesting enzymes should also be considered for cases of possible gluten contamination or gluten ingestion by the CD patient. These consist of special enzymes lacking in the human digestive tract, which can support gluten digestion. Herbal/botanical support to improve the integrity of the epithelial barrier and reduce intestinal permeability should also be provided, as this appears to be a common feature of CD and possibly involved in the pathogenesis of CD, as described above. The use of probiotics should also be considered in cases where there is evidence of dysbiosis or this is suspected.
What role do chronic bacterial and viral infections play in autoimmunity? What role do environmental toxins play? The role of the glutathione and nitric oxide synthase (NOS) systems and development of autoimmunity.
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